Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative

ABSTRACT

The present invention relates to a suspension formulation containing the active substance 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate, to a capsule pharmaceutical dosage form containing said suspension formulation, to a process for preparing said suspension formulation, to a process for preparing said capsule comprising said suspension formulation and to the packaging material for the finished capsule.

The present invention relates to a suspension formulation containing theactive substance3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate,to a capsule pharmaceutical dosage form containing said suspensionformulation, to a process for preparing said suspension formulation, toa process for preparing said capsule comprising said suspensionformulation and to the packaging material for the finished capsule.

BACKGROUND TO THE INVENTION

Some pharmacologically active substances may have biopharmaceuticaland/or physicochemical properties which make them difficult to formulateinto common administration forms. Such substances may be convenientlyadministered in liquid form either in a lipophilic or hydrophiliccarrier system, either as a solution or a suspension, either mixed witha single carrier excipient or mixed with a complex carrier medium madeup of several components. Encapsulation of such liquid formulations insoft gelatin capsules potentially offers a very convenient way ofadministering such pharmacologically active substances.

Solutions

To formulate a solution based system the carrier has to dissolve theactive substance. Improved gastrointestinal (GI) absorption of poorlyabsorbable drugs can be achieved by increasing the dissolution rate ofthe drug in the presence of bile acids. Within the gastrointestinaltract, bile salts behave as biological detergents that, when mixed withphospholipids, form thermodynamically stable mixed micelles. In manyinstances the choice of formulation will be limited by solvent capacity,and in others the drug will not be sufficiently soluble in any lipidformulations.

The carrier medium may be designed to spontaneously form an emulsion ormicroemulsion in the stomach thereby facilitating absorption of thepharmacologically active substance. These systems are commonly known asself (micro-)emulsifying drug delivery systems (SEDDS or SMEDDS). Theyhave to be accurately prepared and even slight variations in thecomposition cannot be tolerated without irreversibly upsetting thesystem, and destroying its beneficial properties. For example, theactive substance may precipitate out as a consequence of a change in thesolubilizing properties of the capsule formulation. This precipitationprocess may be irreversible and lead to an under-dosing of the patient.The emulsifying properties of the capsule formulation may also bechanged, and, upon administration, an emulsion may not be formed in thestomach. As a consequence, the pharmacologically active substance maynot be correctly or reproducibly absorbed.

Suspensions

As suspensions do represent thermodynamic instable multiphase systems,various characteristics have to be taken into account during developmentof these systems. The physical stability of the suspension formulationhas to be ensured from the perspective of particle growth as well asfrom the perspective of re-crystallization in a potential polymorphicform which may have a different solubility or from the perspective ofsedimentation associated by caking of the sediment. These factors mayinfluence the liberation of the active substance from the dosage formand hence alter the extent of patient's exposure during the shelf-lifeof the product. Hence no solubility of the active substance in a singlecarrier excipient or in the carrier system would be the prerequisite fora physically stable system.

Lipophilic Carrier Systems

Lipophilic excipients are commonly employed as moisture barrier systemsto protect chemically instable substances. For this purpose, differenttypes of fats or waxes may be applied on solid dosage forms or on theirmanufacturing intermediates to prevent migration of ambient water vapouror oxygen and to improve the chemical stability of the active substance.Hot-melt inclusions of the drug into lipophilic binders may as wellprevent contact with moisture. Since solid hydrophobic systems poorlydisintegrate, drug release in these systems is delayed, in contrast todrug release in low viscous liquid lipid formulations. This delayed drugrelease is reflected by the specific plasma profiles of the activesubstance of a modified drug delivery system (Ritschel W. et al., DieTablette, 2002, 2nd ed., ECV, Aulendorf, p. 267f). Hence, viscosity ofliquid systems is a crucial parameter and has to be carefully adjustedto ensure adequate drug release.

In practice lipophilic or ‘lipid’ formulations are a diverse group offormulations which have a wide range of properties. These result fromthe blending of up to five classes of excipients, ranging from puretriglyceride oils, through mixed glycerides, lipophilic surfactants,hydrophilic surfactants and water-soluble cosolvents.

Assessment of Quality

The performance of a formulation may be assessed by measuring itsrelative bioavailability, i.e. comparing its bioavailability with thebioavailability of an aqueous solution of the active substance. If thesystems show a comparable bioavailability, not with respect to thedissolution rate but with respect to the drug permeability, pre-systemicor systemic metabolization of the active substance will determine thesystemic exposure. Thus, (lipid) suspensions may also show satisfactoryexposure of the patient due to the adequate solubility of the activesubstance within physiological conditions.

3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonateis an innovative substance having valuable pharmacological properties,especially for the treatment of oncological diseases, immunologicdiseases or pathological conditions involving an immunologic component,or fibrotic diseases.

The chemical structure of this substance is depicted below as Formula(I).

This substance is described as base in WO 01/27081, asmonoethanesulfonate salt form in WO 2004/013099, for its use in thetreatment of immunologic diseases or pathological conditions involvingan immunologic component in WO 2004/017948, for its use in the treatmentof oncological diseases in WO 2004/096224, for its use in the treatmentof fibrotic diseases in WO 2006/067165, and as other salt forms in WO2007/141283.

The aim of the present invention is to obtain for the above drugsubstance an oral pharmaceutical dosage form which meets adequatechemical stability as well as bioavailability requirements for thedesired dosage range tailored to treatment, and a packaging materialsuitable for the product. Such specific pharmaceutical dosage form isnot known from the prior art for this drug substance.

SUMMARY OF THE INVENTION

A first object of the present invention is a formulation of the activesubstance3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonatewhich comprises a suspension of the active substance.

A further object of the present invention is the above formulation inwhich the suspension of the active substance is a viscous suspension of3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonatecomprising a carrier, a thickener and optionally a glidant/solubilizingagent.

A further object of the present invention is the above formulation inwhich the carrier is selected from glycerol, acetylated monoglycerides,corn oil glycerides, caprylic-capric triglycerides, medium chaintriglycerides, medium chain partial glycerides, caprylic/capric/linoleictriglycerides, caprylic/capric/succinic triglycerides, propylene glycoldicaprylate/dicaprate, ethyl oleate, glycerol mono/dioleate, glycerolmonolinolate, macrogolglycerol caprylocaprate, macrogolglycerollinoleate, oleic acid, liquid or semisolid low/intermediate viscouspolyethylene glycols (e.g. polyethylene glycol 300, polyethylene glycol400, polyethylene glycol 600), polyoxyl castor oil, polyoxylhydrogenated castor oil, propylene glycol monocaprylate, propyleneglycol monolaurate, refined animal derived oil, refined soybean oil,refined vegetable oil, sorbitan monostearate, triacetin, triethylcitrate, or mixtures thereof.

In a preferred embodiment in accordance with the present invention, thecarrier is a lipid (lipophilic) carrier.

In a preferred embodiment in accordance with the present invention thecarrier is selected from the following lipid (lipophilic) carriers:acetylated monoglycerides, corn oil glycerides, medium chaintriglycerides, medium chain partial glycerides, caprylic-caprictriglycerides, caprylic/capric/linoleic triglycerides,caprylic/capric/succinic triglycerides, propylene glycoldicaprylate/dicaprate, ethyl oleate, glycerol mono/dioleate, glycerolmonolinolate, macrogolglycerol caprylocaprate, macrogolglycerollinoleate, oleic acid, polyoxyl castor oil, polyoxyl hydrogenated castoroil, propylene glycol monocaprylate, propylene glycol monolaurate,refined animal derived oil, refined soybean oil, refined vegetable oil,sorbitan monostearate, or mixtures thereof.

A further object of the present invention is the above formulation inwhich the thickener is selected from semisolid highly viscous or solidpolyethyleneglycols (e.g. polyethylene 1000 to 20000), preferablypolyethyleneglycols 1000 to 6000, preferably polyethyleneglycol 4000, oroleogel forming excipients, such as Colloidal Silica or Bentonit, orlipophilic or amphiphilic excipients of high viscosity, such as beeswax, glycerol monostearate, hydrogenated vegetable oil, partiallyhydrogenated vegetable oil or hard fats.

In a preferred embodiment in accordance with the present invention, thethickener is selected from oleogel forming excipients, such as ColloidalSilica or Bentonit, or lipophilic or amphiphilic excipients of highviscosity, such as bees wax, glycerol monostearate, hydrogenatedvegetable oil, partially hydrogenated vegetable oil or hard fats.

In a further preferred embodiment, the formulation further comprises aglidant/solubilizing agent.

A further object of the present invention is the above formulation inwhich the glidant/solubilizing agent is selected from lecithin.

A further object of the present invention is the above formulationcomprising a viscous suspension of3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonatein medium chain triglycerides, hard fat and lecithin.

A further object of the present invention is the above formulation whichfurther comprises one or more macrogolglycerols and/or solubilizingagents like lauroyl macrogolglycerides, linoleoyl macrogolglycerides,macrogolglycerol caprylocaprate, macrogolglycerol linolate, oleoylmacrogolglycerides, polyoxyl castor oil, polyoxyl hydrogenated castoroil, polysorbate and propylene glycol monolaurate.

A further object of the present invention is the above formulation,wherein the macrogolglycerols are selected from macrogolglycerolhydroxystearate or macrogolglycerol ricinoleate.

A further object of the present invention is a capsule comprising acapsule shell and a capsule formulation, characterized in that thecapsule formulation comprises the above formulation.

A further object of the present invention is the above capsule,characterised in that the capsule is a soft gelatin capsule.

A further object of the present invention is the above capsule,characterised in that the capsule shell comprises glycerol asplasticizing agent.

A further object of the present invention is a capsule comprising acapsule shell and a capsule formulation, characterized in that thecapsule formulation comprises the above formulation and in that thecapsule is a hard gelatin or a hydroxypropylmethylcellulose (HPMC)capsule, a polyvinyl alcohol polymer capsule or a pullulan capsule,optionally with a sealing or banding.

A further object of the present invention is the above definedformulation or the above defined capsule for use as medicament.

A further object of the present invention is the above definedformulation or the above defined capsule for use as pharmaceuticalcomposition with an antiproliferative activity.

A further object of the present invention is the above definedformulation or the above defined capsule for the treatment of a diseaseor condition selected from oncological diseases, immunologic diseases orpathological conditions involving an immunologic component, and fibroticdiseases.

A further object of the present invention is the use of the abovedefined formulation or the above defined capsule for the preparation ofa medicament for the treatment of a disease or condition selected fromoncological diseases, immunologic diseases or pathological conditionsinvolving an immunologic component, and fibrotic diseases.

A further object of the present invention is a process for the treatmentand/or prevention of a disease or condition selected from oncologicaldiseases, immunologic diseases or pathological conditions involving animmunologic component, and fibrotic diseases, characterised in that aneffective amount of the above defined formulation or the above definedcapsule is administered orally to a patient once or several times daily.

A further object of the present invention is the above definedformulation or the above defined capsule for use in a dosage range offrom 0.1 mg to 20 mg of active substance/kg body weight, preferably 0.5mg to 4 mg active substance/kg body weight.

A further object of the present invention is a glass container orflexible/hard plastic container suitable for the packaging of capsules,containing one or more of the above defined capsules.

A further object of the present invention is an aluminium pouch ordouble poly bag suitable for the packaging of capsules, containing oneor more of the above defined capsules.

A further object of the present invention is a plastic (e.g. PVC, PVDCor Aclar®) blister suitable for the packaging of capsules, containingone or more of the above defined capsules, optionally with anover-packaging of an aluminium pouch.

A further object of the present invention is an aluminium blistersuitable for the packaging of capsules, containing one or more of theabove defined capsules.

LEGEND TO THE FIGURES

FIG. 1—Mass gain by moisture sorption (Dm in %) under different relativehumidity conditions (r.H. in %) for a soft gelatin capsule (A) and for alipid suspension formulation (B).

FIG. 2—Effect of the employed lecithin amount on the in-vitrodissolution behaviour (in % of dissolution) over time (in minutes) ofsoft gelatin capsules: (A) 30% lecithin of preferred amount, (B) 75%lecithin of preferred amount, (C) 90% lecithin of preferred amount, (D)preferred amount of lecithin (equals to 100%), (E) 200% lecithin ofpreferred amount, (F) 0% lecithin.

FIG. 3—Effect of the melting range of the hard fat on the in-vitrodissolution behaviour (in % of dissolution) over time (in minutes) ofsoft gelatin capsules: (A) melting range of 33° C.-40° C., (B) meltingrange of 40° C.-44° C.

FIG. 4—Comparison of the absolute bioavailability (BA in %) tested inthe rat over 24 hours for the aqueous solution (S) versus differentcarrier systems (P1, P2 and P3) of the active substance—Error barsindicate standard deviations.

DETAILED DESCRIPTION OF THE INVENTION

It has been found that, surprisingly, a soft gelatin capsule including aliquid formulation comprising a viscous suspension of3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonatein medium chain triglycerides, hard fat and lecithin, meets the adequatebioavailability requirements for the desired dosage range tailored totreatment with the drug substance3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate.This liquid formulation consists of a lipid suspension of the activesubstance.

An advantage of such soft gelatin capsule containing a lipid suspensionis that the water uptake into the formulation is very unlikely. Thedosage form is divided into three different compartments, namely (a) ahydrophilic capsule shell and (b) the hydrophobic carrier system inwhich (c) the slightly hygroscopic powder of active substance issuspended. Due to ambient moisture the content of water may vary withinthese different compartments. It will migrate by diffusion until anequilibrium state is reached. The water content may affect differentproperties of the drug product, such as the chemical stability of theactive substance (predominantly via hydrolysis) or the elasticity of thecapsule shell. The water uptake in the present system is primarily inthe capsule shell. This can be shown by water vapour sorptionexperiments (shown in FIG. 1) as well as by the correlation of the massgain with the softening of the capsule. The water uptake does furthernot affect the chemical stability of the drug substance. This isconfirmed by the stress stability studies of, for example, 1 month at70° C., and by the long-term (3 years) and accelerated (6 months)stability study results for the systems in accordance with the presentinvention.

Furthermore, studies have shown that there is no mass increase orsticking problem for the capsules in accordance with the presentinvention when stored in tight packaging materials. Thus, recommendedpackaging for such capsules are, for example, alu/alu blisters and HDPEbottles.

Generally, soft gelatin capsules have a capsule shell made of gelatin,one or more plasticizing agents, in particular glycerol, optionallyfurther auxiliary materials, such as dyes, colorant pigments, flavouringagents, sugar, oligosaccharides or polysaccharides, and a capsuleformulation (or capsule filling) containing a solvent, adjuvants and oneor more pharmacologically active substances. The term gelatin as usedherein includes not only unmodified gelatin as in the EuropeanPharmacopeia but also modified gelatin, such as for example succinatedgelatin.

As already mentioned hereinbefore, the present invention relates to alipid suspension formulation of the active substance3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate.

In a preferred embodiment in accordance with the present invention, thelipid suspension formulation of the active substance3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonatecomprises a viscous suspension of3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonatein a lipid carrier, a thickener and a glidant/solubilizing agent.

In a further preferred embodiment in accordance with the presentinvention, the amount of3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonateis comprised within the range of 1 to 90 weight % of the lipidsuspension formulation, preferably within 10 and 50%.

To avoid the above-mentioned physical stability issues, such asre-crystallization or particle-growth, the active substance must beeither completely insoluble or dissolved in the carrier. A solubilityscreening of lipophilic hydrophilic and amphiphilic excipients andmixtures revealed various potential carriers for formulating the lipidsuspension in accordance with the present invention. The choice of theselipid carriers for the lipid suspension in accordance with the presentinvention represents a further object of the present invention.

Thus, in a preferred embodiment, suitable carriers or carrier componentsfor the active substance3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonateare acetylated monoglycerides, corn oil glycerides, ethyl oleate,glycerol mono/dioleate, glycerol monolinolate, macrogolglycerolcaprylocaprate, macrogolglycerol linoleate, medium chain partialglycerides, medium chain triglycerides, caprylic-capric triglycerides,caprylic/capric/linoleic triglycerides, caprylic/capric/succinictriglycerides, propylene glycol dicaprylate/dicaprate, oleic acidpolyoxyl castor oil, polyoxyl hydrogenated castor oil, propylene glycolmonocaprylate, propylene glycol monolaurate, refined animal derived oil,refined soybean oil, refined vegetable oil, sorbitan monostearate,triacetin, triethyl citrate, or mixtures thereof.

Stability issues such as hydrolytic degradation of the active substancemay also be caused by hydrophilic carrier components. Therefore, carriersystems based on hydrophilic polyethylene glycols will generally showinferior stability than more hydrophobic carriers such as lipidcarriers.

In accordance with the present invention, the most preferred lipidcarrier is medium chain triglycerides. It is comprised within the rangeof 1 to 90 weight % of the lipid suspension formulation, preferablywithin 10 and 70%. Suitable medium chain triglycerides may be thecommercial product Miglyol 812®, Miglyol 810®, Miglyol 818®, Miglyol829® or Miglyol 840®.

A thickener adjusts the viscosity of the suspension. It stabilizes thesuspension system, ensures optimal processing and guarantees an adequatecapsule quality, especially as far as content uniformity or dissolutionbehaviour are concerned. In a preferred embodiment, suitable thickenersto be used in the present invention are oleogel forming excipients, suchas Colloidal Silica or Bentonit, or lipophilic or amphiphilic excipientsof high viscosity, such as bees wax, glycerol monostearate, hydrogenatedvegetable oil, partially hydrogenated vegetable oil or hard fats.

In accordance with the present invention, the most preferred thickeneris hard fat. It is preferably comprised within the range of 1 to 30weight % of the suspension formulation, most preferably within 10 and 30weight %. The most suitable hard fats have a melting range of 30° C. to44° C., most preferably a melting range of 33° C. to 40° C. Suitablecommercially available products are Gelucire® 33/01, Witepsol®W35 orSoftisan® 378. The determination of the most suitable melting range forhard fats can be performed as shown in FIG. 3, by measurement of theeffect of the melting range of the hard fat on the in-vitro dissolutionbehaviour over time.

Lecithin is a common excipient for carrier-systems in soft gelatincapsules. It is used as a glidant of the highly concentrated suspensionduring encapsulation, prevents blocking of ducts and pumps and ensureshigh mass uniformity of the encapsulated formulation. FurthermoreLecithin acts as a surfactant, which may improve distribution of theformulation-droplets during in-vitro dissolution testing as well asin-vivo for drug resorption. Furthermore it may also improve wetting ofthe active substance crystals. Suitable lecithin may be the commercialproduct Topcithin®.

It was surprisingly found that lecithin, up to a certain content, isuseful to improve the dissolution behaviour of the finished capsules.Exceeding amounts do not show an additional benefit during in-vitrodissolution testing, as shown in FIG. 2.

In a preferred embodiment in accordance with the present invention, theamount of lecithin is comprised within the range of 0.1 to 10 weight %of the lipid suspension formulation, most preferably within 0.25 and2.5%.

In an alternative embodiment, the present invention relates to a lipidsuspension formulation of the active substance3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate,comprising a viscous suspension of3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonatein medium chain triglycerides, hard fat, lecithin and one or moremacrogolglycerols, such as for example macrogolglycerol-hydroxystearate(traded for example under the name Eumulgin® HRE 40 PH) ormacrogolglycerol-ricinoleate (also known as polyoxyl castor oil andtraded for example under the name Cremophor® EL, Cremophor® RH40 orEumulgin® RO 35 PH).

In a preferred embodiment in accordance with the present invention, theamount of macrogolglycerol(s) is comprised within the range of 0.1 to 50weight % of the lipid suspension formulation, most preferably within 0.3and 10%.

Three carrier systems (the hydrophilic P3, lipophilic P1 and lipophilicwith surfactants P2 semi-solid suspension formulations described in theforegoing) were tested for bioavailability in non-clinical studies andall of them were identified to be suitable options for an oral dosageform of the active substance3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate.

However, for reasons of bioavailability, as is evident from the resultsshown in FIG. 4, lipid (lipophilic) suspension formulations comprising aviscous suspension of3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonatein medium chain triglycerides, hard fat and lecithin are preferred.

Hence, FIG. 4 shows the results of a comparison of the absolutebioavailability (BA in %) tested in the rat over 24 hours for theaqueous solution (S) versus different carrier systems (P1, P2 and P3) ofthe active substance in accordance with the present invention. Theexperiment is described in the following.

The table below shows the composition of the tested carrier systems(semi-solid suspension formulations).

Formulation P1 P2 P3 Ingredients [%]* Active Substance 43.48 42.19 31.75Triglycerides, 37.83 41.77 — Medium-Chain Hard fat 18.26 12.66 —Cremophor RH40 — 2.95 — Lecithin  0.43 0.42 — Glycerol 85% — — 3.17Purified Water — — 4.76 Macrogol 600 — — 58.10 Macrogol 4000 — — 2.22*slight deviations of the quantities towards 100 percent may be causedby rounding errors

The semi-solid suspensions are filled in hard gelatin capsules(Capsugel, no. Y0303490). Each capsule contains approximately 15 to 20mg of the formulation. The capsules are applied to the rats with aspecial device similar to gavage. For comparison an aqueous solutioncontaining 0.5% Natrosol 250 FIX is applied via gavage. For calculationof the absolute bioavailability an additional group of rats is dosedintravenously with the compound dissolved in 5% glucose solution(aqueous solution (S)). 5 male Han Wistar rats (strain: CrlGlxBrlHan:WI)are used per group. Blood sampling times are 0.5 h, 1 h, 2 h, 4 h, 8 h,24 h post dose and plasma is analysed by a validated HPLC/MS/MS method.From the plasma level time curves areas under the curve (AUC) arecalculated by linear trapezoidal rule. Dose normalised AUCs of the oralformulation are divided by dose normalised AUCs of the intravenousformulation for the calculation of the absolute bioavailability. As canbe seen from the results of the experiment shown in FIG. 4, thebioavailability is similar for the aqueous solution (S: 11%) and thedifferent carrier systems of active substance (P1: 14%, P2: 10% and P3:10%), however the inter-individual variation (standard deviation ofbioavailability) is smaller for the aqueous solution (S) and the carriersystem (P1) when compared to the carrier systems (P2) and (P3) (2.8 and4.1 versus 7.4 and 7.1), indicating a practically complete relativebioavailability for the tested formulations (P1, P2 and P3) versus thesolution (S) but a higher variation in the carrier systems (P2) and(P3).

The present invention further relates to a capsule pharmaceutical dosageform consisting of a capsule shell and a capsule formulation (or capsulefilling), characterized in that the capsule formulation (or capsulefilling) comprises the lipid suspension formulation as hereinbeforedescribed. The capsule pharmaceutical dosage form may be a soft gelatinecapsule, a hard gelatine capsule, or an hydroxypropylmethylcellulose(HPMC) capsule or a polyvinyl alcohol polymer capsule or a pullulancapsule.

In the case of a hard gelatine capsule or anhydroxypropylmethylcellulose (HPMC) capsule, a polyvinyl alcohol polymercapsule or a pullulan capsule, the filled in capsule may further besealed or banded.

In a preferred embodiment in accordance with the present invention, thecapsule is a soft gelatin capsule consisting of a capsule shellcomprising gelatin, one or more plasticizing agents and optionallyfurther auxiliary materials, and a capsule formulation (or capsulefilling), characterized in that the capsule formulation (or capsulefilling) comprises the lipid suspension formulation as hereinbeforedescribed.

The capsule pharmaceutical dosage form according to the invention, andespecially the soft gelatin capsules, may be stored in suitable glasscontainers or in flexible/hard plastic containers, preferably non-PVCmaterials based, or in plastic (e.g. PVC, PVDC or Aclar®) blistersoptionally with an over-packaging of aluminium (aluminium pouch), or inaluminium blisters consisting of e.g a bottom foil of PA/Al/PVC and analuminium lidding foil, the later providing the highest waterprotection. Hence, the containers may be designed so as to provideparticular protection for the capsule pharmaceutical dosage formaccording to the invention, and especially the soft gelatin capsules,e.g. to protect them from light, oxygen or water. Flexible plasticcontainers may contain additional protection, e.g. in the form of anadditional aluminium packaging.

The capsule pharmaceutical dosage form according to the invention may beprepared by conventional methods of producing capsules known from theliterature. The soft gelatin capsule according to the invention may beprepared by conventional methods of producing soft gelatin capsulesknown from the literature, such as for example the “rotary dieprocedure”, described for example in Swarbrick, Boylann, Encyclopedia ofpharmaceutical technology, Marcel Dekker, 1990, Vol. 2, pp 269 ff or inLachmann et al., “The Theory and Practice of Industrial Pharmacy”, 2ndEdition, pages 404-419, 1976, or other procedures, such as thosedescribed for example in Emerson R. F. et al., “Soft gelatin capsuleupdate”, Drug Dev. Ind. Pharm., Vol. 12, No. 8-9, pp. 1133-44, 1986.

The lipid suspension formulation may be prepared by conventional methodsof producing formulations known from the literature, i.e. by mixing theingredients at a pre-determined temperature in a pre-determined order inorder to obtain a homogenized suspension.

Alternatively, the lipid suspension formulation may be prepared inaccordance with the procedure described in Example 10, which is also anobject of the present invention

Lipid suspension formulation of the active substance, finished softgelatin capsules containing same and packaging materials for thepackaging of finished soft gelatin capsules according to the inventionare illustrated by the Examples and Figures that follow. The Examplesserve purely as an illustration and are not to be construed in alimiting capacity.

Examples of Carrier Systems (Formulations), Soft Gelatin Capsules,Packaging Materials, and of a Manufacturing Process for the Preparationof a Lipid Suspension Formulation of the Active Substance

The active substance in all the Examples is3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate.

EXAMPLE 1

Lipid Based Carrier System

Formulation A B C Ingredients [%]* Active Substance 43.48 43.48 43.48Triglycerides, 28.70 37.83 38.045 Medium-Chain Hard fat 27.39 18.2618.26 Lecithin 0.43 0.43 0.215 *slight deviations of the quantitiestowards 100 percent may be caused by rounding errors

EXAMPLE 2

Lipid Based Carrier System with Additional Surfactant

Ingredients [%]* Active Substance 42.19 Triglycerides, 41.77Medium-Chain Hard fat 12.66 Cremophor RH40 2.95 Lecithin 0.42 *slightdeviations of the quantities towards 100 percent may be caused byrounding errors

EXAMPLE 3

Hydrophilic Carrier System

Ingredients [%]* Active Substance 31.75 Glycerol 85% 3.17 Purified Water4.76 Macrogol 600 58.10 Macrogol 4000 2.22 *slight deviations of thequantities towards 100 percent may be caused by rounding errors

EXAMPLE 4

Soft Gelatin Capsule Containing 50 mg of Active Substance

Formulation Formulation Formulation A B C mg per mg per mg perIngredients Function capsule capsule capsule Active Active 60.20 60.2060.20 Substance* Ingredient Triglycerides, Carrier 40.95 53.70 54.00Medium-chain Hard fat Thickener 38.25 25.50 25.50 Lecithin Wetting 0.600.60 0.30 agent/ Glidant Gelatin Film- 72.25 72.25 72.25 former Glycerol85% Plasticizer 32.24 32.24 32.24 Titanium Colorant 0.20 0.20 0.20dioxide Iron oxide A Colorant 0.32 0.32 0.32 Iron oxide B Colorant 0.320.32 0.32 Total Capsule 245.33 245.33 245.33 Weight *The figures referto the amount of ethanesulfonate salt (dry basis) equivalent to thelabeled amount of the free base

EXAMPLE 5

Soft Gelatin Capsule Containing 100 mg of Active Substance

Formulation Formulation Formulation A B C mg per mg per mg perIngredients Function capsule capsule capsule Active Active 120.40 120.40120.40 Substance* Ingredient Triglycerides, Carrier 81.90 107.40 106.8Medium-chain Hard fat Thickener 76.50 51.00 51.00 Lecithin Wetting 1.201.20 1.80 agent/ Glidant Gelatin Film- 111.58 111.58 111.58 formerGlycerol 85% Plasticizer 48.79 48.79 48.79 Titanium Colorant 0.36 0.360.36 dioxide Iron oxide A Colorant 0.06 0.06 0.06 Iron oxide B Colorant0.17 0.17 0.17 Total Capsule 440.96 440.96 440.96 Weight *The figuresrefer to the amount of ethanesulfonate salt (dry basis) equivalent tothe labeled amount of the free base

EXAMPLE 6

Soft Gelatin Capsule Containing 125 mg of Active Substance

Formulation Formulation Formulation A B C mg per mg per mg perIngredients Function capsule capsule capsule Active Active 150.50 150.50150.50 Substance* Ingredient Triglycerides, Carrier 102.375 134.25 133.5Medium-chain Hard fat Thickener 95.625 63.75 63.75 Lecithin Wetting 1.501.50 2.25 agent/ Glidant Gelatin Film- 142.82 142.82 142.82 formerGlycerol 85% Plasticizer 62.45 62.45 62.45 Titanium dioxide Colorant0.47 0.47 0.47 Iron oxide A Colorant 0.08 0.08 0.08 Iron oxide BColorant 0.22 0.22 0.22 Total Capsule 556.04 556.04 556.04 Weight *Thefigures refer to the amount of ethanesulfonate salt (dry basis)equivalent to the labeled amount of the free base

EXAMPLE 7

Soft Gelatin Capsule Containing 150 mg of Active Substance

Formulation Formulation Formulation A B C mg per mg per mg perIngredients Function capsule capsule capsule Active Active 180.60 180.60180.60 Substance* Ingredient Triglycerides, Carrier 122.85 161.10 160.20Medium-chain Hard fat Thickener 114.75 76.50 76.50 Lecithin Wetting 1.801.80 2.70 agent/ Glidant Gelatin Film- 142.82 142.82 142.82 formerGlycerol 85% Plasticizer 62.45 62.45 62.45 Titanium dioxide Colorant0.47 0.47 0.47 Iron oxide A Colorant 0.08 0.08 0.08 Iron oxide BColorant 0.22 0.22 0.22 Total Capsule 626.04 626.04 626.04 Weight *Thefigures refer to the amount of ethanesulfonate salt (dry basis)equivalent to the labeled amount of the free base

EXAMPLE 8

Soft Gelatin Capsule Containing 200 mg of Active Substance

Formulation Formulation Formulation A B C mg per mg per mg perIngredients Function capsule capsule capsule Active Active 240.80 240.80240.80 Substance* Ingredient Triglycerides, Carrier 163.30 214.80 216.00Medium-chain Hard fat Thickener 153.50 102.00 102.00 Lecithin Wetting2.40 2.40 1.20 agent/ Glidant Gelatin Film- 203.19 203.19 203.19 formerGlycerol 85% Plasticizer 102.61 102.61 102.61 Titanium Colorant 0.570.57 0.57 dioxide Iron oxide A Colorant 0.90 0.90 0.90 Iron oxide BColorant 0.90 0.90 0.90 Total Capsule 868.17 868.17 868.17 Weight *Thefigures refer to the amount of ethanesulfonate salt (dry basis)equivalent to the labeled amount of the free base

EXAMPLE 9

Packaging materials for the packaging of the soft gelatin capsules ofabove examples 4 to 8 may be glass containers, flexible/hard plasticcontainers or PVC/PVDC blisters, optionally within an aluminium pouch,or alu/alu blisters.

EXAMPLE 10

In the following, a manufacturing process for the preparation of a lipidsuspension formulation of the active substance and a process for theencapsulation are described.

-   a: Hard fat and parts of Medium-chain triglycerides are pre-mixed in    the processing unit. Subsequently lecithin, the rest of medium-chain    triglycerides and the active substance are added. The suspension is    mixed, homogenized, de-aerated and finally sieved to produce the    formulation (Fillmix)-   b. The gelatin basic mass components (glycerol, water and gelatine)    are mixed and dissolved at elevated temperature. Then, the    corresponding colours are added and mixed, producing the Coloured    Gelatin Mass.-   c. After adjustment of the encapsulation machine, Fillmix and    Coloured Gelatin Mass are processed into soft gelatin capsules using    the rotary-die process. This process is e.g. described in Swarbrick,    Boylann, Encyclopedia of pharmaceutical technology, Marcel Dekker,    1990, Vol. 2, pp 269 ff.-   d. The initial drying is carried out using a rotary dryer. For the    final drying step, capsules are placed on trays. Drying is performed    at 15-26° C. and low relative humidity.-   e. After 100% visual inspection of the capsules for separation of    deformed or leaking capsules, the capsules are size sorted.-   f. Finally, the capsules are imprinted, using an Offset printing    technology or an Ink-jet printing technology. Alternatively, the    capsule imprint can be made using the Ribbon printing technology, a    technology in which the gelatin bands are imprinted prior to the    encapsulation step c.

1. Formulation of the active substance3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonatewhich comprises a suspension of the active substance.
 2. Formulationaccording to claim 1, in which the suspension of the active substance isa viscous suspension of3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonatecomprising a carrier and a thickener.
 3. Formulation according to claim2 in which the carrier is selected from acetylated monoglycerides, cornoil glycerides, ethyl oleate, glycerol mono/dioleate, glycerolmonolinolate, glycerol, macrogolglycerol caprylocaprate,macrogolglycerol linoleate, medium chain partial glycerides, mediumchain triglycerides, caprylic-capric triglycerides,caprylic/capric/linoleic triglycerides, caprylic/capric/succinictriglycerides, propylene glycol dicaprylate/dicaprate, oleic acid,liquid or semisolid low/intermediate viscous polyethylene glycols,polyoxyl castor oil, polyoxyl hydrogenated castor oil, propylene glycolmonocaprylate, propylene glycol monolaurate, refined animal derived oil,refined soybean oil, refined vegetable oil, sorbitan monostearate,triacetin, and triethyl citrate, or mixtures thereof.
 4. Formulationaccording to claim 2 in which the thickener is selected from semisolidhighly viscous or solid polyethyleneglycols, oleogel forming excipients,lipophilic or amphiphilic excipients of high viscosity, and hard fats.5. Formulation according to claim 2 in which the carrier is a lipid(lipophilic) carrier.
 6. Formulation according to claim 2 which furthercomprises a glidant/solubilizing agent.
 7. Formulation according toclaim 6 in which the glidant/solubilizing agent is selected fromlecithin.
 8. Formulation according to claim 7, comprising a viscoussuspension of3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonatein medium chain triglycerides, hard fat and lecithin.
 9. Formulationaccording to claim 1, which further comprises one or moremacrogolglycerols and/or solubilizing agents.
 10. Formulation accordingto claim 9, wherein the macrogolglycerols are selected frommacrogolglycerol hydroxystearate or macrogolglycerol ricinoleate. 11.Capsule comprising a capsule shell and a capsule formulation,characterized in that the capsule formulation comprises the formulationin accordance with claim
 1. 12. Capsule according to claim 11,characterised in that the capsule is a soft gelatin capsule.
 13. Capsuleaccording to claim 11, characterised in that the capsule shell comprisesglycerol as plasticizing agent.
 14. Capsule according to claim 11,characterised in that the capsule is a hard gelatin or ahydroxypropylmethylcellulose (HPMC) capsule, a polyvinyl alcohol polymercapsule or a pullulan capsule, optionally with a sealing or banding. 15.Process for the treatment and/or prevention of a disease or conditionselected from oncological diseases, immunologic diseases or pathologicalconditions involving an immunologic component, and fibrotic diseases,characterised in that an effective amount of a formulation according toany one of claims 1 to 10 or capsule according to any one of claims 11to 14 is administered orally to a patient once or several times daily.16. Formulation according to any one of claims 1 to 10 or capsuleaccording to any one of claims 11 to 14 for use in a dosage range offrom 0.1 mg to 20 mg of active substance/kg body weight.
 17. One or morecapsules according to any one of claims 11 to 14 in a glass container orflexible/hard plastic container suitable for the packaging of capsules.18. One or more capsules according to any one of claims 11 to 14 in aplastic blister, optionally with an over-packaging of aluminium, oraluminium blister suitable for the packaging of capsule.